Transcript Components of Neonatal Outcome in Diabetes in Pregnancy

Metabolic and Stress
Components of Neonatal
Outcome
Josephine Carlos-Raboca
Section Chief,
Endocrinology Diabetes and Metabolism
Makati Medical Center
Metabolic and Stress Components of Neonatal
Outcome
Josephine Carlos-Raboca, MD,FPCP, FPSEM
Makati Medical Center
Cradle to cradle
 Health
begins in the womb
 Mother to baby to mother to baby
 It comes in several full circles
Outline
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Fetal Programming
Neonatal Outcomes
Metabolic Components-Nutrition as major determinant
> Glucose and Diabetes
> Lipids
> Maternal Weight Gain
Stress in Utero
Modifying Outcomes
Fetal Programming
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Fetal stage is a time of plasticity
Environment that nurtures fetal development is
largely dictated by the mother
Development is modified by exposure to
nutrition, stress and other factors in utero
influenced by genetic make up
Lifelong changes of adult disease
Nutrition and Neonatal Outcome
Undernutrition - small for gestational age
Overnutrition - large for gestational age
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glucose
lipids
amino acids
Mechanism of Programming
Fetal programming
Genetic
predisposition
CVD, INSULIN
RESISTANCE
Environmental
factors
Thrifty Gene/ Barker’s
Hypothesis/Fetal Origin Theory
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Growth in utero has profound effects on adult
health
Undernutrition has permanent effects
Small for gestational age at risk for diabetes
mellitus type 2, hypertension, coronary artery
disease
Death rates from CVD according to birth
weight modified from Barker 1996 (n=15726)
Birth weight(kg)
<2.5
Standardized
mortality ratio
100
Number of
deaths
57
2.95
81
137
3.41
80
298
3.86
74
289
4.31
55
103
>4.31
65
57
total
74
941
DUTCH FAMINE COHORT
STUDIES
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malnutrition of daily caloric consumption <1000
increased adiposity in later life in female
offspring
Earlier onset of CAD (HR 1.9 47 y vs 50 y)
Early gestation exposure was associated with an
excess in dyslipidemia, more obesity in women,
higher CAD and breast cancer
Mid and late gestation raised 2 hour glucose
concentrations and insulin concentrations
Association Of Low Birth Weight and Diabetes
Mellitus 2 in Young Filipino Adults
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81 young diabetics vs 82 control, 18-37 years old
LBW <2500g (13% vs 2%) OR %>%
Low birth weight < 2500g, adult obesity and a positive
family history of DM 2 were associated with an
increased risk for type 2 DM
Obrero, Raboca,Litonjua,. PJIM 2006 gm%
Summary for Undernutrition fetal
programming
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Undernutrition in gestation induces
programming of the pancreatic beta cell,
muscle, liver, adipose tissues and
neuroendocrine axis
Mismatch of poor prenatal environment and
rich postnatal environment leads to
maladaptation
Leads to glucose intolerance , obesity and
coronary disease in adult life
Nutrient supply > demand
Glucose Oversupply
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Maternal hormonal and metabolic alteration in
GDM modify in- utero environment leading to
abnormal fetal growth
Impaired fetal development has severe metabolic
consequences with increased risk to develop
glucose intolerance and obesity in adolescence
and later life
Pedersen’s Theory
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1950 - maternal glucose leads to fetal
hyperinsulinemia and fetal overgrowth Increase
Macrosomia-Pathogenesis
Macrosomic Newborn (4.2kg)
www.drsarma.in
26
The Hyperglycemia and Adverse
Pregnancy Outcome (HAPO)
Is there a glycemic threshold for maternal and neonatal
adverse effects?
very large, international , randomized, observational
study
To clarify the risks of adverse outcomes associated with
various degrees of maternal glucose intolerance less
severe than in overt diabetes
Methods
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25,502 pregnant women at 15 centers in 9
countries
75 g OGTT at 0,1h,2 h test at 24-32 weeks of
gestation
Data blinded if FPG < 105 mg/dl(5.8mmol/l)
RPG <160 mg/dl
2 HPG < 200 mg/dl(11.1mmol/l)
Unblinded if RPG < 45 mg/dl(2.5 mmol/l)
Outcomes
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Primary: birth weight >90th centile
primary CS
clinical neonatal hypoglycemia
cord blood serum c-peptide >90th centile
Secondary : Premature delivery <37 weeks of gestation
Shoulder dystocia or birth injury
need for intensive neonatal care
hyperbilirubinemia
pre-eclampsia
Results
Continuous variable analysis
 Odds ratio calculated
for 1-SD in
birth weight cord blood
>90%
C-peptide>90%
 fasting /6.9 mg/dl
1.38
1.55
 1h,
/30.9 mg/dl
1.46
1.46
 2h
/23.8 mg/dl
1.38
1.37
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Glucose categories
fasting
1 hour
2 hour
<75
<105
<90
75-79
106-132
91-108
80-84
133-155
109-125
85-89
156-171
126-139
90-94
172-193
140-157
95-99
194-211
158-177
100 and more
212 and more
178 and more
Results:
Conclusions
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Risk of macrosomia, neonatal hypoglycemia and
neonatal hyperinsulinemia increase with blood glucose
in a continuum over the entire range of blood glucose
levels
Neonatal hyperinsulinemia and large babies were noted
even in blood glucose levels considered normal
Maternal glucose measured at a single point in
pregnancy is effective in predicting birth outcome
HAPO follow up study
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Antropometric measures associated with cord c-peptide
were assessed using logistic regression analysis
Adjusted for confounders
Maternal glucose is associated with increased
C –peptide and neonatal obesity in a continuous
manner
Confirms Pedersen’s Theory
Diabetes 58; 453-459, 2009
Conclusions
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Risk of macrosomia, neonatal hypoglycemia and
neonatal hyperinsulinemia increase with blood glucose
in a continuum over the entire range of blood glucose
levels with no clear cut off levels
Neonatal hyperinsulinemia and large babies were noted
even in blood glucose levels considered normal
Weight Gain
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Excessive weight gain increases risks:
> Diabetes
> Preecclampsia
> Bigger babies
> C sections
> Birthing injuries
Maternal Fetal Outcomes in Asians
Raboca et al 2003 JAFES
Fetal overgrowth – Frenkel and
Metzger 1980
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nutrients other than glucose led to fetal
overgrowth as well but hyperinsulinemia and
glucose control had primary roles
Fate of Early Lesions in Children
(FELIC)
 156
children 1-13 y/o
 Atherosclerosis progress faster in those whose
mothers who were hypercholesterolemic during
pregnancy
 Hypothesis: lipid levels exert constitutive
changes on gene expression in arterial lining
and influence later CVD
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Napoli, Lancet 1999
Long term outcome of GDM babies
Increasing prevalence of obesity and diabetes in
childhood and adolescence
 1994 Obesity 14%/ overweight 12% in adolescents
Ogden et al JAMA 2002:288,1728-1732
 NHANES 1999-2000 obesity 30.3% in 6-11years old.
Incidence of DM2 among adolescents
 1982 5%
 1999 45%
Kaufman J Ped Endoc Metab 2002: 15, 737-744.
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Association of Intrauterine exposure to
maternal diabetes and obesity with
T2DM and obesity in youth
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10-22 years old
Dm 2 <20 years of age
79 diabetic youth vs 190 non diabetic control
Exposure to diabetes and obesity recalled by
biological mother
Adjusted for offspring age, sex, ethnicity
Dabalea et al Diabetes Care 31; 1422-1426,2008
Factors associated with hypertension and
DM2 in childhood
Longitudinal cohort study in American Pima Indians
 Birth Weight
large for gestationl age
small for gestational age
Exposure to diabetes in utero
Obesity
Pettitt et al Am J Epid 1994:140:123-131.
GDM may lead to Dysregulation of
Adipoinsular Axis in offspring
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cross sectional study of 116 Polynesian, South
Asian women in New Zealand
Leptin levels are increased with increased birth
weight in offspring of mothers with GDM
Leads to leptin resistance, obesity and DM2
Simmons et al Diabetes Care 225:1539-1544, 2002.
Stress and Neonatal Outcome
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Altered ACTH and cortisol response to acute
social and pharmacologic damage
Altered HPA-axis feedback sensitivity
LBW asso with elevated basal cortisol
concentrations and increased adrenocortical
responsiveness to ACTH at adult age
Altered setpoint resulting in an increased activity
and secretion of glucocorticoids asso with
insulin resistance
What can we do to prevent cycle?
insulin resistance
(GDM)
obesity
DM2
Obesity
GDM
CVD
Australian Carbohydrate Intolerance
Study (ACHOIS)
490 women with GDM at 24-34 weeks gestation
randomized to intervention treatment (dietary
advice, blood glucose monitoring and insulin
treatment)
510 randomized to routine care.
Primary outcome – serious perinatal complications
NEJM 2005,353;2477-86
Australian Carbohydrate Intolerance
Study (ACHOIS)
NEJM 2005,353;2477-86
Women 24-34 weeks gestation with GDM 490
randomized to intervention treatment (dietary
advice, blood glucose monitoring and insulin
treatment)
510 randomized to routine care.
Primary outcome – serious perinatal complications
Results
Intervention group vs routine care
 Perinatal complications was significantly lower
1% vs 4%
p = 0.01
 More infant admissions to neonatal nursery
71% vs 61% p=0.01
 Higher induced labor rate
39% vs 29% p=<0.001
 Similar cesarean delivery
31% vs 32%
Results
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At 3 months post partum
lower rates of depression, higher scores for
quality of life consistent with improved health
status in intervention group vs routine care
Conclusions
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Treatment of gestational diabetes reduces
perinatal morbidity and may also improve the
woman’s health related quality of life.
A Multicenter Randomized Trial of Treatment
for Mild Gestational Diabetes
NICHD-MFMU
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958 pregnant women
100 gm OGTT 24-31 weeks of gestation
485 randomized to treatment
473 to control group
Landon et al NEJM October 2009
A Multicenter Randomized Trial of Treatment
for Mild Gestational Diabetes
NICHD-MFMU
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Primary outcome: stillbirth or perinatal death
and neonatal complications as
hyperbilirubinemia hyperinsulinemia and birth
trauma
Secondary outcomes
large for gestational age, small for gestational
age, respiratory distress syndrome,admission to
neonatal intensive care unit
Perinatal and Neonatal Outcomes
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No significant difference between the treatment
group and control group in the frequency of the
primary outcomes
No perinatal death in both groups.
Secondary outcomes
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Significant reductions in LGA in treatment
group
No significant difference in SGA
MFMU secondary outcomes
Treatment grp
Routine care
Mean birth weight 3302 g
3408 g
Neonatal fat mass 427 g
464 g
LGA
7.1%
14.5%
BW>4000g
5.9%
14.3%
Conclusions MFMU Study
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Although treatment of mild gestational diabetes
mellitus did not significantly reduce the
frequency of a composite outcome that included
stillbirth or perinatal death and several neonatal
complications, it did reduce the risks of fetal
overgrowth shoulder dystocia, cesarian delivery
and hypertensive disorders
Recommendations
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Daily consumption 0f 8-12 fruit and vegetable servings, 3 low fat
dairy servings, 5-9 0z of protein rich foods, 6-10 whole grain
servings and 3-7 tsp of healthy fat as olive oil canola oil or nuts.
Eating regular meals and small healthy snacks between meals
Fat portion of less than 30% 0f caloric intake
Decrease intake of sweets and sweetened drinks
Use of food diary to monitor nutritional adequacy and portion
size
Limiting caloric intake to 10 to 300 extra calories per day beyond
prepregnancy caloric needs
30minute exercise on most days after consulting with healthcare
provider regarding how to start an exercise program
Recommended weight gain for
prepregnancy BMI
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Underweight<18.5
kg/m2
Normal weight 18.5-24.9
kg/m2
Overweight 25-29.9
kg/m2
Obese>30kg/m2
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28-40lbs
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25-35 lbs
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15-25lbs
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11-20 lbs
Conclusions
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Fetal Programming occurs early in utero.
This is determined by genes, nutrition, stress and
maternal health.
Undernutrition mainly measured by small for gestation
age leads to organ programming adapted to poor
environment referred to as a thrifty gene. Exposed to
rich nutrtition post natally leads to maladaptation,
obesity, coronary artery disease and diabetes mellitus
type 2.
This has been shown by Barker and in the Dutch
Famine Cohort Studies.
Conclusions
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Similarly, overnutrition mainly studied in
gestational diabetes also leads to fetal
programming that leads to obesity and diabetes
mellitus type 2 in adult life in a different
mechanism.
LGA has been shown to result from GDM in
the major study , HAPO
Conclusions
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Stress in utero can come in many forms from
infection, trauma, psychosocial stress to mother,
and even nutritional stress.
Stress induces changes in the hypothalamic
adrenal axis either by setting a different setpoint
or altered sensitivity causing higher
glucocorticoid production, obesity and
metabolic problems in adult life.
Conclusions
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Preventive health therefore starts early from
prepregnancy to pregnancy with emphasis on
proper nutrition, adequate weight gain and stress
control.
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Thank You